The Experimental Pathology core will provide the necessary infrastructure, technical and professional[unreadable] support to perform pathologic and molecular analyses of mouse and human pancreatic ductal neoplasms..[unreadable] Detailed histopathologic examinations of genetically engineered mice (GEM) will be performed to identify[unreadable] tumors, characterize whether they display pancreatic ductal differentiation and identify the presence of[unreadable] metastases. The following models will be analyzed: GEM with Kras activation and combinations of p53,[unreadable] Ink4a/Arf and/or Smad4 inactivation (Project 1); GEM targeting PI3 kinase pathway components (Project 2);[unreadable] GEM (from Project 1 and 2) entered into preclinical chemotherapeutic trials (Project 3); and GEM[unreadable] constructed to assess early lesions and cell of origin (Project 4).[unreadable] A central goal is to understand the morphologic progression of mouse pancreatic neoplasms. Duct[unreadable] epithelial lesions, including the size, extent, grade and multifocality of pancreatic intraepithelial neoplasms[unreadable] (PanlNs) will be assessed in each model and correlated with genotype to delineate the biologic role of[unreadable] specific genetic lesions in morphologic progression. Correlations will be made with findings from the Imaging[unreadable] Core to refine the results of novel diagnostic strategies. The Core will also support the immunohistochemical[unreadable] analysis of mouse neoplasms including signature pancreatic pathways (Project 1), PI3 kinase signaling[unreadable] (Project 2), tumor microenvironment (Project 3) and tumor stem cell compartments (Project 4). Novel[unreadable] monoclonal antibodies for use in immunohistochemical assays will be developed in conjunction with the[unreadable] Antibody Core. Putative amplicon genes for new models will be screened in human samples by FISH.[unreadable] The validity of these models will be examined by characterizing these same pathways and cell[unreadable] compartments in human pancreatic ductal adenocarcinomas and PanlNs. Provisions of human tissue[unreadable] samples and their analysis will be performed in collaboration with the BioBank Core, and will test the[unreadable] hypothesis that GEM models may yield important insights into human pancreatic carcinogenesis.[unreadable] These investigations of mice engineered to develop pancreatic tumors will define the genetic basis of[unreadable] mouse tumor development, providing advances in understanding of human pancreatic cancer, and leading to[unreadable] systems for the testing of new therapies specifically targeting biologic pathways.[unreadable]